This Independent Scientist Award application requests support for a newly independent scientist who has demonstrated a commitment to a career in biomedical research since 1992, particularly in the area of immunopathogenesis of lentiviral mucosal transmission. A successful R01 application followed by acceptance of a tenure track position has the candidate poised to continue her immunopathogenesis studies, initiate new programs to further develop intervention strategies using the feline immunodeficiency virus (FIV) infection animal model, and build collaborative relationships. The objective of this application is to provide salary support, over five years, to reduce the clinical component of the candidate's current tenure-track appointment, thus allowing a period of intensive research focus to foster her scientific development, and expanding her potential to make significant research contributions. The candidate is in a highly supportive environment with excellent mentors, numerous opportunities for intellectual development, and several central equipment laboratories. The candidate's research focus concerns the role of cell-associated virus in mucosal transmission, tissue tropism, early immune induction, and intervention and/or protective strategies. The core research project (a five-year R01 funded 7/2/99) consists of three specific aims. Specific Aim 1 will use fluorescent labeled, FIV-infected peripheral blood mononuclear cells (PBMCs) to identify the cells responsible for transvaginal FIV infection. The relative efficiency of vaginal transmission by lymphocytes and macrophages will be determined by vaginal inoculation of serially diluted FACS sorted cell populations. Specific Aim 2 will determine whether the early pathogenesis of cell-associated vaginal transmission is altered by unique targets (e.g. vaginal epithelium) or immunologic selection. Specific Aim 3 tests the ability of a lymphoid targeting vector (Venezuelan equine encephalitis replicon particles) to induce FIV-specific vaginal immunity. FIV expressing replicon particles will be used to identify the optimal route of immunization to induce strong cell-mediated immunity in the vaginal mucosa. Vaginal challenge with cell-associated FIV will test the correlates of protection.